SGLT2 inhibitors and GLP-1 receptor agonists in atrial fibrillation treatment: Clinical evidence and mechanistic insights

Atrial fibrillation (AF) is the most common sustained arrhythmia globally. Despite certain progress in drug and interventional treatments, AF still presents high morbidity, high mortality, and unsatisfactory clinical outcomes. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), initially used to treat type 2 diabetes mellitus (T2DM), have demonstrated cardiorenal protective effects beyond glycemic control and have drawn broad attention for their potential in AF management. This narrative review comprehensively synthesizes clinical evidence and underlying mechanisms regarding the effects of SGLT2i and GLP-1 RA on new-onset AF and post-ablation AF recurrence across common comorbidities, including T2DM, heart failure (HF), chronic kidney disease (CKD) and obesity. Available evidence shows that SGLT2i may be associated with reduced new-onset AF risk in patients with T2DM, HF and CKD, and lower post-ablation AF recurrence in high-risk groups. GLP-1 RA show beneficial effects on AF in individuals with obesity or heart failure with preserved ejection fraction. Their protective effects are mainly mediated by upstream metabolic regulation and direct effects on atrial electrophysiology, as evidenced by cellular, animal, and clinical studies. Notably, most clinical evidence comes from post hoc analyses and observational studies, with AF rarely as a primary endpoint and without systematic measurement, leaving the evidence at a hypothesis-generating stage with limited clinical applicability. Overall, SGLT2i and GLP-1 RA serve as potential adjunctive therapies for AF patients with concomitant cardiometabolic comorbidities. Their AF-related outcomes represent exploratory secondary benefits instead of established therapeutic indications. Further specific randomized controlled trials (RCTs) with prespecified AF endpoint and standardized AF monitoring are needed to verify their clinical efficacy and application prospects.